Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) are severe drug-induced cutaneous reactions, with keratinocyte apoptosis characterized to be the primary histologic feature1. Exosomes are nanometre-sized vesicles with a lipid bilayer membrane and present in body fluids, containing functional proteins, mRNAs and miRNAs, which induce immune dysfunction and influence disease progress2.Nevertheless, the potential roles of plasma exosomes and the underlying mechanisms in the context of severe drug eruptions have yet to be explored.
Here we observed that exosomes isolated from plasma of SJS/TEN patients showed the expected size between 30 and 150nm, and shown to be positive for exosomal markers CD9, CD63, CD81 and TSG101. Deep sequencing analysis and qRT-PCR of plasma exosomal derived miRNAs demonstrated that the miR-375-3p level was the markedly upregulated in SJS/TEN patients and was positively correlated with clinical features. Moreover, miR-375-3p was mainly expressed in the epidermal apoptotic keratinocytes of SJS/TEN patients. Then, plasma derived exosomes from patients were internalized by human primary keratinocytes and promoted the cell apoptosis. Additionally, transfection of the miR-375-3p mimic into keratinocytes resulted in increased the proportion of apoptotic cells via mitochondrial pathway. Besides, the miR-375-3p mimic also downregulated the expression of X-linked inhibitor of apoptosis protein (XIAP). Lastly, overexpression of XIAP attenuated miR-375-3p mimic-mediated apoptosis of keratinocytes.

Plasma exosomal miR-375-3p regulates mitochondria-dependent apoptotic pathway in keratinocytes by targeting XIAP in SJS/TEN